Zinc deficiency and advanced liver fibrosis among HIV and hepatitis C co-infected anti-retroviral naïve persons with alcohol use in Russia.

BACKGROUND AND AIMS: Liver disease in people living with HIV co-infected with hepatitis C virus is a source of morbidity and mortality in Russia. HIV accelerates liver fibrosis in the setting of HCV co-infection and alcohol use. Zinc deficiency is common among people living with HIV and may be a factor that facilitates the underlying mechanisms of liver fibrosis. We investigated the association between zinc deficiency and advanced liver fibrosis in a cohort of HIV/HCV co-infected persons reporting heavy drinking in Russia. METHODS: This is a secondary data analysis of baseline data from 204 anti-retroviral treatment naïve HIV/HCV co-infected Russians with heavy drinking that were recruited into a clinical trial of zinc supplementation. The primary outcome of interest in this cross-sectional study was advanced liver fibrosis. Zinc deficiency, the main independent variable, was defined as plasma zinc <0.75 mg/L. Exploratory analyses were performed examining continuous zinc levels and fibrosis scores. Analyses were conducted using multivariable regression models adjusted for potential confounders. RESULTS: The prevalence of advanced liver fibrosis was similar for those with zinc deficiency compared to those with normal zinc levels, (27.7% vs. 23.0%, respectively). We did not detect an association between zinc deficiency and advanced liver fibrosis in the adjusted regression model (aOR: 1.28, 95% CI: 0.62-2.61, p = 0.51) nor in exploratory analyses. CONCLUSIONS: In this cohort of Russians with HIV/HCV co-infection, who are anti-retroviral treatment naïve and have heavy alcohol use, we did not detect an association between zinc deficiency or zinc levels and advanced liver fibrosis.

Characterization of an Inducible Alcoholic Liver Fibrosis Model for Hepatocellular Carcinoma Investigation in a Transgenic Porcine Tumorigenic Platform.

PURPOSE: This study used the Oncopig Cancer Model (OCM) to develop alcohol-induced fibrosis in a porcine model capable of developing hepatocellular carcinoma. MATERIALS AND METHODS: Liver injury was induced in 8-week-old Oncopigs (n = 10) via hepatic transarterial infusion of 0.75 mL/kg ethanol-ethiodized oil (1:3 v/v). Feasibility was assessed in an initial Oncopig cohort (n = 5) by histologic analysis at 8 weeks after induction, and METAVIR results were compared to age- and sex-matched healthy controls (n = 5). Liver injury was then induced in a second OCM cohort (n = 5) for a time-course study, with post-induction disease surveillance via biweekly physical exam, lab analysis, and liver biopsies until 20 weeks after induction. RESULTS: In Cohort 1, 8-week post-induction liver histologic analysis revealed median METAVIR F3 (range, F3-F4) fibrosis, A2 (range, A2-A3) inflammation, and 15.3% (range, 5.0%-22.9%) fibrosis. METAVIR and inflammation scores were generally elevated compared to healthy controls (F0-F1, P = 0.0013; A0-A1, P = .0013; median percent fibrosis 8.7%, range, 5.8%-12.1%, P = .064). In Cohort 2, histologic analysis revealed peak fibrosis severity of median METAVIR F3 (range, F2-F3). However, lack of persistent alcohol exposure resulted in liver recovery, with median METAVIR F2 (range, F1-F2) fibrosis at 20 weeks after induction. No behavioral or biochemical abnormalities were observed to indicate liver decompensation. CONCLUSIONS: This study successfully validated a protocol to develop METAVIR F3-F4 fibrosis within 8 weeks in the OCM, supporting its potential to serve as a model for hepatocellular carcinoma in a fibrotic liver background. Further investigation is required to determine if repeated alcohol liver injury is required to develop an irreversible METAVIR grade F4 porcine cirrhosis model.

Aldehyde dehydrogenase 2 polymorphism for development to hepatocellular carcinoma in East Asian alcoholic liver cirrhosis.

BACKGROUND AND AIM: We aimed to clarify the influences of aldehyde dehydrogenase 2 (ALDH2), alcohol dehydrogenase 1B (ADH1B) polymorphisms, and ethanol consumption profile to hepatocellular carcinoma (HCC) development in alcoholic liver cirrhosis without chronic hepatitis B and C virus infection (non-B non-C). METHODS: Of 236 freshly diagnosed non-B non-C alcoholic liver cirrhosis patients, 67 were diagnosed as HCC and the remaining 169 as not having HCC. The relationship between the genetic polymorphisms and development to HCC were evaluated in well-matched patients with HCC (HCC group, n = 67) and without HCC (non-HCC group, n = 67) using propensity scores in age, sex, and prevalence of diabetes mellitus. RESULTS: Daily amount of ethanol consumption was significantly lower (P = 0.005), and consumptive period was significantly longer (P = 0.003) in HCC group than non-HCC group. Of 134 well-matched patients, 113 (84.3%) had ALDH2*1/*1 genotype and 21 (15.7%) had ALDH2*1/*2 genotype. In HCC development, consumptive long period (P = 0.007) and carrying ALDH2*1/*2 genotype (P = 0.026) were identified as significant factors independently participated, while there was no relation to ADH1B polymorphism. In addition, consumptive period was significantly longer in HCC group than non-HCC group in ALDH2*1/*1 genotype patients (P = 0.0005), while there was no difference in profile of ethanol consumption in ALDH2*1/*2 genotype patients. Among HCC group, daily (P = 3.78 × 10(-6) ) and cumulative amount (P = 4.89 × 10(-6) ) of ethanol consumption were significantly higher in ALDH2*1/*1 genotype patients than ALDH2*1/*2 genotype patients. CONCLUSION: In alcoholic liver cirrhosis, investigations of ALDH2 polymorphism and ethanol consumption profile are useful for prediction of HCC development.

Liver abnormalities in drug and substance abusers.

Drug and substance abuse remains a major medical problem. Alcohol use, abuse and dependence are highly prevalent conditions. Alcohol related liver disease can present as simple steatosis, steatohepatitis, alcoholic hepatitis or liver cirrhosis. Paracetamol hepatotoxicity secondary to accidental or deliberate overdose is another common problem. While the adverse cardiovascular, neurological, renal and psychiatric consequences of various illicit substance abuses are widely studied and publicized, less attention has been directed towards possible hepatotoxic effects. Illicit drug abuse can cause a range of liver abnormalities ranging from asymptomatic derangement of liver function tests to fulminant hepatic failure. This article reviews the epidemiology, risk factors, clinical manifestations, pathogenesis, investigations, management and prognostic factors of alcohol related liver disease and paracetamol hepatotoxicity as well as the current knowledge pertaining to hepatotoxicity of the more commonly used illicit substances including cannabis, amphetamine type stimulants, cocaine, khat chewing and complementary and alternate medicine.

[Primary and secondary prevention of alcoholic liver cirrhosis].

Alcohol--is the main causative factor of cirrhosis among the population in Russia. The primary prevention must be focused on exception of consumption of heavy doses of alcohol hepatitis and B vaccination. There are no healthy doses of alcohol. Secondary prevention means the use of the hepatoprotectors. List of hepatoprotectors and also amount of money spent to the purchase of these hepatoprotectors increase constantly. But, unfortunately, alongside with it, increases the mortality from hepatic disorders. Effectiveness of the most hepatoprotectors (such as Essential phospholipids, milk thistle) equals to the effectiveness of placebo.

Ascorbic acid is superior to silymarin in the recovery of ethanol-induced inflammatory reactions in hepatocytes of guinea pigs.

Both oxidative stress and inflammatory reactions play a major role in alcoholic liver fibrosis. We evaluated the efficacy of ascorbic acid (AA) and silymarin in the regression of alcohol-induced inflammation in hepatocytes of guinea pigs (Cavia porcellus). Animals were administered with ethanol at a daily dose of 4 g/kg body weight (b.wt) for 90 days. On the ninety-first day, ethanol administration was stopped and animals were divided into alcohol abstention group and silymarin- (25 mg/100 g b.wt) and AA- (25 mg/100 g b.wt) supplemented groups and maintained for 30 days. There was a significant increase in the activities of alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase in the serum of the ethanol group. The intracellular reactive oxygen species (ROS) and expressions of cytochrome P4502E1 and nuclear factor κB1, tumor necrosis factor-α, and transforming growth factor-ß(1) in hepatocytes were significantly increased in ethanol group. The fibrotic markers α-smooth muscle actin and α(1)(I) collagen and activity of cytotoxicity marker caspase-3 were significantly increased and AA content was significantly reduced in hepatocytes of alcohol-treated guinea pigs. But the AA and silymarin supplementation significantly reduced these changes in comparison with alcohol abstention group. AA could induce greater reduction of inflammatory and fibrotic markers in hepatocytes than silymarin. This indicates that AA is superior to silymarin in inhibiting intracellular ROS generation and thereby reducing the ethanol-induced inflammation in hepatocytes.

Glycine prevents hepatic fibrosis by preventing the accumulation of collagen in rats with alcoholic liver injury.

We studied the effect of administering glycine, a non-essential amino acid, on liver collagen content and its characteristics in experimental hepatotoxic Wistar rats. All the rats were fed standard pellet diet. Hepatotoxicity was induced by orally administering ethanol (7.9 g kg(-1)) for 30 days. Control rats were given isocaloric glucose solution. Glycine was administered subsequently at a dose of 0.6 g kg(-1) po every day, along with alcohol for the next 30 days. Alcohol administration significantly elevated the levels of liver hydroxyproline and total collagen content, cross-linked fluorescence, shrinkage temperature and lipid peroxidation, whereas it significantly decreased the solubility of liver collagen as compared with the control rats. Simultaneous glycine supplementation to alcohol-fed rats significantly reduced the levels of liver hydroxyproline and total collagen content, cross-linked fluorescence, shrinkage temperature and lipid peroxidation and enhanced the solubility of liver collagen as compared with the unsupplemented alcohol-fed rats. In conclusion, administration of glycine had a positive influence both on the quantitative and qualitative properties of hepatic collagen in alcoholic liver injury.

CD14 and lipopolysaccharide binding protein expression in a rat model of alcoholic liver disease.

Lipopolysaccharide-binding protein (LBP) and CD14 play key intermediary roles in the activation of cells by endotoxin. As endotoxin has been postulated to participate in promoting pathological liver injury in alcoholic liver disease, we investigated the role of LBP and CD14 in alcoholic liver injury. Rats were fed intragastrically ethanol or dextrose and either medium-chain triglycerides, corn oil, or fish oil for 4 weeks. Kupffer cells, endothelial cells, and hepatocytes were isolated. LBP and CD14 mRNA levels were measured in liver and individual cell types. The highest levels of LBP and CD14 mRNA levels in the liver were found in the fish oil/ethanol group, which was also the group with the greatest degree of pathological injury and inflammation. CD14 mRNA levels were also significantly elevated in groups fed unsaturated fatty acids with dextrose. CD14 expression was localized to the Kupffer cells and LBP expression to the hepatocytes. Expression of CD14 mRNA was also found in nonmyeloid cells in the two experimental groups (fish oil/ethanol and corn oil/ethanol) that had liver necrosis and inflammation. Our results suggest that enhanced LBP and CD14 expression correlates with the presence of pathological liver injury in alcoholic liver injury. Furthermore, unsaturated fatty acids may prime cells to respond to endotoxin by enhancing CD14 expression.

The effects of low dietary levels of polyunsaturates on alcohol-induced liver disease in rhesus monkeys.

Rhesus monkeys that were maintained on a diet containing low, yet adequate, amounts of vitamins C and E and in which linoleate and linolenate represented 1.4% and 0.08% of the total caloric intake, respectively, developed liver fibrosis after consuming alcohol (mean, 2.6 g kg(-1) d[-1]) over a period of 3 years. In the liver, several polyunsaturated fatty acids including 18:2n6, 20:4n6, and 22:6n3 decreased compared with dietary controls, and similar findings were also observed in plasma lipoproteins and erythrocytes. The amount of alcohol consumed correlated positively with plasma lipid peroxidation products, 4-hydroxynonenal (4-HNE) and 8-isoprostane F2alpha, and negatively with 20:4n6 and 22:6n3 levels. These findings imply that alcoholics who also have a marginal intake of essential fatty acids and antioxidants in their diets may be at an increased risk of developing liver disease.

Experimental liver cirrhosis induced by alcohol and iron.

To determine if alcoholic liver fibrogenesis is exacerbated by dietary iron supplementation, carbonyl iron (0.25% wt/vol) was intragastrically infused with or without ethanol to rats for 16 wk. Carbonyl iron had no effect on blood alcohol concentration, hepatic biochemical measurements, or liver histology in control animals. In both ethanol-fed and control rats, the supplementation produced a two- to threefold increase in the mean hepatic non-heme iron concentration but it remained within or near the range found in normal human subjects. As previously shown, the concentrations of liver malondialdehyde (MDA), liver 4-hydroxynonenal (4HNE), and serum aminotransferases (ALT, AST) were significantly elevated by ethanol infusion alone. The addition of iron supplementation to ethanol resulted in a further twofold increment in mean MDA, 4HNE, ALT, and AST. On histological examination, focal fibrosis was found < 30% of the rats fed ethanol alone. In animals given both ethanol and iron, fibrosis was present in all, with a diffuse central-central bridging pattern in 60%, and two animals (17%) developed micronodular cirrhosis. The iron-potentiated alcoholic liver fibrogenesis was closely associated with intense and diffuse immunostaining for MDA and 4HNE adduct epitopes in the livers. Furthermore, in these animals, accentuated increases in procollagen alpha 1(I) and TGF beta 1 mRNA levels were found in both liver tissues and freshly isolated hepatic stellate cells, perisinusoidal cells believed to be a major source of extracellular matrices in liver fibrosis. The dietary iron supplementation to intragastric ethanol infusion exacerbates hepatocyte damage, promotes liver fibrogenesis, and produces evident cirrhosis in some animals. These results provide evidence for a critical role of iron and iron-catalyzed oxidant stress in progression of alcoholic liver disease.

A comparison of nutritional profiles of patients with alcohol-related pancreatitis and cirrhosis.

A multifactorial study of 58 variables of alcohol, dietary and tobacco habits of 106 chronic alcoholic and normal subjects was conducted over 2 years. The alcoholic population included subjects with either calcifying chronic pancreatitis (CCP) or cirrhosis (Ci). A standardized, previously validated questionnaire was used to investigate dietary intakes, drinking and smoking habits. The patients with CCP consumed a richer diet than those with Ci, consisting mainly of saturated fats and animals proteins. Although the alcoholics with CCP drank the same total quantity of alcohol as the alcoholics with Ci, they drank it over a shorter time period (less than 20 years) before diagnosis. Differences in the nutritional profiles of the two groups indicate that the population with alcohol-related digestive diseases is made up of subjects with different drinking and eating habits. These behavioural differences with respect to dietary and alcohol intake indicate that the alcoholic patients with CCP or Ci belong to different subgroups.

[Treatment of acute alcoholic alcoholism]. / Le traitement de l'hépatite alcoolique aiguë.

Acute alcoholic hepatitis is the first alcoholic lesion of the liver in the process of progression to cirrhosis. It is due to the toxic action of alcohol on hepatocytes, in particular in the centrolobular region. It may affect a liver which is the site of fatty infiltration, fibrosis or cirrhosis, i.e. during all the stages of alcoholic liver disease. Its severity depends upon the degree of alcoholic intoxication. It may be fatal by malignant hepatic failure in a quarter of cases or, at the extreme, be totally asymptomatic. The aims of treatment are: 1) in the immediate, to prevent death; 2) subsequently, to prevent progression to cirrhosis. The majority of the wide range of treatments suggested have been evaluated in controlled trials. It is thus easy to show that corticosteroids are effective in severe acute alcoholic hepatitis, i.e. with encephalopathy and coagulation disturbances, but no in ordinary forms. Although logical, nutritional supplements, whether enteral or parenteral, have no influence on the course of acute alcoholic hepatitis. The same applies to anabolic steroids, the association insulin-glucagon, antifibrosis agents or "hepatoprotectors". The elimination of alcoholic intoxication remains the most important point, accepted by all hepatologists.

Alcohol, smoking, coffee, and cirrhosis.

Since most heavy drinkers do not develop alcoholic cirrhosis, other causes or predisposing factors are probable. The authors studied traits of 128,934 adults who underwent health examinations at the Oakland and San Francisco, California, facilities of the Kaiser Permanente Medical Care Program from January 1978 to December 1985 in relation to subsequent hospitalization or death from cirrhosis of the liver. In analyses adjusted for nine covariates, past and current alcohol drinking were strongly related to cirrhosis risk, but usual choice of alcoholic beverage had no independent relation. Cigarette smoking was independently related to risk of alcoholic cirrhosis, with cigarette smokers of a pack or more per day at trebled risk compared with lifelong nonsmokers. Coffee drinking, but not tea drinking, was inversely related to alcoholic cirrhosis risk, with persons who drank four or more cups per day at one-fifth the risk of noncoffee drinkers. This inverse relation between coffee consumption and risk of alcoholic cirrhosis was consistent in many subsets, including persons free of gastrointestinal disease and those with 5 or more years before hospitalization or death. Cigarette smoking and coffee consumption were not consistently related to risk of hospitalization or death for nonalcoholic cirrhosis. These data could mean that cigarette smoking promotes alcoholic cirrhosis and that coffee drinking might be protective.

Alcohol, liver, and nutrition.

Until two decades ago, dietary deficiencies were considered to be the major reason why alcoholics developed liver disease. As the overall nutrition of the population improved, more emphasis was placed on secondary malnutrition. Direct hepatotoxic effects of ethanol were also established, some of which were linked to redox changes produced by reduced nicotinamide adenine dinucleotide (NADH) generated via the alcohol dehydrogenase (ADH) pathway. It was also determined that ethanol can be oxidized by a microsomal ethanol oxidizing system (MEOS) involving cytochrome P-450: the newly discovered ethanol-inducible cytochrome P-450 (P-450IIE1) contributes to ethanol metabolism, tolerance, energy wastage (with associated weight loss), and the selective hepatic perivenular toxicity of various xenobiotics. P-450 induction also explains depletion (and enhanced toxicity) of nutritional factors such as vitamin A. Even at the early fatty-liver stage, alcoholics commonly have a very low hepatic concentration of vitamin A. Ethanol administration in animals was found to depress hepatic levels of vitamin A, even when administered with diets containing large amounts of the vitamin, reflecting, in part, accelerated microsomal degradation through newly discovered microsomal pathways of retinol metabolism, inducible by either ethanol or drug administration. The hepatic depletion of vitamin A was strikingly exacerbated when ethanol and other drugs were given together, mimicking a common clinical occurrence. Hepatic retinoid depletion was found to be associated with lysosomal lesions and decreased detoxification of chemical carcinogens. To alleviate these adverse effects, as well as to correct problems of night blindness and sexual inadequacies, the alcoholic patient should be provided with vitamin A supplementation. Such therapy, however, is complicated by the fact that in excessive amounts vitamin A is hepatotoxic, an effect exacerbated by long-term ethanol consumption. This results in striking morphologic and functional alterations of the mitochondria with leakage of mitochondrial enzymes, hepatic necrosis, and fibrosis. Thus, treatment with vitamin A and other nutritional factors (such as proteins) is beneficial but must take into account a narrowed therapeutic window in alcoholics who have increased needs for such nutrients, but also display an enhanced susceptibility to their adverse effects. Massive doses of choline also exerted some toxic effects and failed to prevent the development of alcoholic cirrhosis. Acetaldehyde (the metabolite produced from ethanol by either ADH or MEOS) impairs hepatic oxygen utilization and forms protein adducts, resulting in antibody production, enzyme inactivation, and decreased DNA repair. It also enhances pyridoxine and perhaps folate degradation and stimulates collagen production by the vitamin A storing cells (lipocytes) and myofibroblasts.(ABSTRACT TRUNCATED AT 400 WORDS)

Chronic administration of ethanol with high vitamin A supplementation in a liquid diet to rats does not cause liver fibrosis. 1. Morphological observations.

Rats of two strains (BN/BiRij and WAG/Rij) were fed the ethanol-containing Lieber-De Carli liquid diet supplemented with high amounts of vitamin A for 16 months. In contrast to Lieber and co-workers, who showed liver fibrosis developing within 9 months on the same diet in Sprague-Dawley rats, we were unable to demonstrate a histological and biochemical increase in liver collagen in either strain. Steatosis was present to a varying degree in both strains in ethanol-treated rats, but also in control animals. Considerable liver inflammation with focal necrosis accompanied by severe systemic inflammation was observed in 60% of the ethanol-treated WAG rats. This suggests that, at least in rats, the main effects of chronic ethanol consumption on the liver may be secondary to interference with host resistance to infections. The ethanol-high vitamin A Lieber-De Carli liquid diet does not necessarily elicit fibrosis or other characteristic histological abnormalities of human alcoholic liver disease.

Chronic administration of ethanol with high vitamin A supplementation in a liquid diet to rats does not cause liver fibrosis. 2. Biochemical observations.

The inability of the 'ethanol/high vitamin A Lieber-DeCarli diet' to induce liver fibrosis in two different rat strains was further evaluated by determining changes in parameters of liver cell damage and of retinoid and lipid metabolism. In the ethanol/vitamin A-treated group, slight but constant hepatic cell damage, as indicated by elevated alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase activities in blood, was already observed at 6 months and maintained until the time of death at 16 months. Serum gamma-glutamyl transaminase activities were not raised. Moderate parenchymal liver cell damage was not accompanied by fibrosis. Hypertriglyceridemia or hypercholesterolemia were observed at 6-16 months of chronic alcohol administration. This response was strain dependent. In ethanol-treated rats of both strains, total liver retinoids and serum retinol concentrations were not altered. Therefore, the hypothesis that interaction between alcohol and retinoids is a major factor in the pathogenesis of alcoholic liver disease, needs to be reconsidered.

Alcohol and nutrition: caloric value, bioenergetics, and relationship to liver damage.

Alcoholic beverages contribute an appreciable percentage (4-6%) to the total caloric intake in Western societies. The caloric value of ethanol as fuel may be dose-related. Most evidence suggests that at moderate intake levels of less than 45 g/day (3 drinks) ethanol is efficiently utilized as a fuel by the liver. At high intakes, ethanol calories may not be utilized for cellular synthesis of ATP and maintenance of weight. The exact mechanism for this inefficient utilization remains unknown but may be related, in part, to metabolism of ethanol by the microsomal ethanol-oxidizing system, a reaction that does not contribute to generation of reducing equivalents for ATP synthesis. Although ethanol is utilized for ATP synthesis after single-dose administration, chronic consumption leads to morphological changes in hepatic mitochondria and to decreased ATP synthesis. Reductions in the activities of the enzymes of the mitochondrial electron transport chain have been reported after alcohol feeding and may help to explain decreases in hepatic ATP synthesis. There is some evidence that ATP degradation by "Na-K ATPase" is increased after ethanol feeding and that hepatic O2 consumption is likewise enhanced. However, other studies have failed to demonstrate enhanced O2 consumption. Current evidence suggests that malnutrition alone is not sufficient to explain the pathogenesis of chronic liver disease in alcoholics. Although the daily amount of alcohol consumed and the duration of excessive consumption are clearly important factors in the development of alcoholic hepatitis and cirrhosis, other factors, particularly nutritional deficiencies, may modulate the risk of developing alcohol-related liver damage. The prevalence of malnutrition is exceedingly high in alcoholics with clinically severe liver disease. Nutritional deficiencies are better correlated with a clinical index of severity than with histologic severity of alcoholic hepatitis. Prognosis and outcome of patients with alcoholic liver disease may be affected by nutritional deficiencies, which thus provides a rationale for aggressive nutritional management of these patients.